Systemic lupus erythematosus (SLE) afflicts 1 to 2 million Americans and is associated with significant morbidity and mortality. While the overall survival and quality of life has improved during the last 30 years, we still lack specific treatmen, full understanding of the involved pathogenic mechanisms and proper disease biomarkers. T cells missing CD4 and CD8 from the surface (CD3+CD4-CD8-) are expanded in patients with SLE and they can help autologous B cells to produce autoantibodies, produce interleukin-17 and infiltrate tissue to instigate inflammation. CD3+CD4-CD8- may arise from CD8+ cells following epigenetic closure of the CD8 locus. Building on data generated during the last cycle, this proposal will test the hypothesis that CD3+CD4-CD8- cells originate from CD8 cells upon encountering antigen, produce proinflammatory cytokines and enter target tissues. In three integrated but independent sets of experiments we will 1) define the epigenetic requirements that lead to the generation of CD3+CD4-CD8- cells in patients with SLE and lupus prone mice and further define their metabolic status; 2) determine how interleukin-2 suppresses and interleukin-17 expands the generation of DN cells in lupus-prone mice, and 3) study determinants of CD3+CD4-CD8- entry in to the kidney. The proposal introduces state-of-the-art techniques to 1) study the epigenetic closure of CD8 which leads to the expansion of CD3+CD4-CD8- cells, 2) understand their metabolic profile and 3) to visualize their entry in to the kidney. Conceptually, the studies introduce epigenetics and metabolomics to help understand the nature of pathogenic T cell subset in SLE patients. The proposed studies are significant because the numbers of circulating CD3+CD4-CD8- cells may represent a biomarker as they may enter tissues to cause damage and because control of their generation and metabolic profile and interference with their entry to tissues should reveal therapeutic options.